PI/PD: Jain, Nitya Ph.D. PROJECT SUMMARY The immune system faces unique challenges in early life. In utero, the developing fetal immune system must tolerate myriad maternal antigenic exposures including nutrients and xenobiotics that are transferred across the placenta. At birth, the still developing immune system of the newborn is abruptly exposed to a multitude of environmental and microbial antigens and must rapidly form a discrimination of friend from foe. The early life immune system itself undergoes rapid and radical changes during this time that are driven by these antigenic events and the action of transcription factor regulatory circuits directing the development and effector programming of specific immune cell types. The period immediately after birth thus represents a unique immune state with significant overlap of fetal and postnatally derived immune cells. Thus, there is great interest in understanding the genetic program underlying these developmental transitions that determine quality of immune cells being generated over ontogeny. In preliminary experiments, a comparison of gene expression profiles of developing thymic cells from neonatal and adult mice by RNA-seq identified the gene Igf2bp3 to be highly expressed in early life. The goal of this R21 application is to explore the role of IGF2BP3 in early life T cell development. Using novel mouse models that we have generated, we will determine the precise expression of IGF2BP3 over ontogeny and the consequences of deletion of IGF2BP3 in thymic precursor cells on T cell development and function. These foundational studies will shed light on the makeup of the immune repertoire during the period of overlap of fetal and postnatal immune cells and strive to understand the nature of immune responses during this transitional period.